In the previous grant period, we discovered that neuropeptide Y (NPY), a sympathetic co-transmitter, when applied at the side of angioplasty-injured carotid artery in normolipemic rats, leads to fast vessel occlusion with vascularized neointima, containing matrix, thrombus, macrophages and lipids, and resembling advanced atherosclerotic lesion. NPY's effect is prevented by NPY receptor (R) antagonists (Y1 and Y5) and occurs at concentrations similar to those yielded by stress. Angioplasty alone up-regulates vascular expression of NPY Rs. NPY stimulates vascular smooth muscle cell (VSMC) contraction and proliferation, angiogenesis, causes obesity and hyperlipemia, and is also a platelet-derived factor and immunomodulator. Recently, a common Leu7/Pro7-NPY signal peptide gene polymorphism in Europeans, producing a more releasable peptide, is found to associate with increased total and LDL cholesterol and accelerated atherosclerosis. Considering these convergent basic and clinical data, we now seek to determine/3" NPYpromotes atherosclerosis, and if so, by what mechanisms. We hypothesize that NPY is pro-atherosclerotic by stimulating several steps of atherosclerosis. The role of endogenous NPY and its specific Rs will be determined using animals fed high fat diet with or without angioplasty in i) rats over-expressing NPY (NPY-Tg); ii) mice null for NPY, Y1, Y5 or YI+Y5 R; iii) mice with and without platelet NPY over-expression, and 4) ApoE-/- mice treated with NPY R antagonists. AIMs are to test if 1) NPY and its specific Rs increase neointima formation and atherosclerosis; 2) platelet-derived NPY augments platelet aggregability, and VSMC contraction and growth; 3) NPY stimulates macrophage migration, lipid uptake, lipoprotein lipase activity and foam cell formation; and 4) YI-Y5R oligomerization regulates NPY's receptor properties and, hence, pro-atherosclerotic actions. To relate these data to humans, the association of the Leu7/Pro7 polymorphism with vascular NPY R expression and atherosclerosis will also be studied in human atherosclerotic and non-atherosclerotic vessels. [unreadable] [unreadable] [unreadable]